A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene () causing pyruvate dehydrogenase complex deficiency.

Unlabelled: Congenital lactic acidosis due to pyruvate dehydrogenase phosphatase (PDP) deficiency is very rare. PDP regulates pyruvate dehydrogenase complex (PDC) and defective PDP leads to PDC deficiency. We report a case with functional PDC deficiency with low activated (+dichloroacetate) and inactivated (+fluoride) PDC activities in lymphocytes and fibroblasts, normal activity of other mitochondrial enzymes in fibroblasts, and novel biallelic frameshift mutation in the gene, c.

Scorpiurus aramoana (Diptera: Dolichopodidae), a new species from New Zealand.

The New Zealand endemic genus Scorpiurus Parent is known from marine littoral habitats. A new species, S. aramoana sp.

Improved cardiac outcomes with combined atenolol and diazepam intervention in seizure.

Objective: Altered autonomic activity has been implicated in the development of cardiac dysfunction during seizures. This study investigates whether intervening in seizure progression with diazepam will reduce seizure-induced cardiomyopathy. Second, this study examines the hypothesis that combining atenolol with diazepam, as an intervention after seizure onset, will combat cardiac injury during status epilepticus.

Enzymatic testing sensitivity, variability and practical diagnostic algorithm for pyruvate dehydrogenase complex (PDC) deficiency.

Pyruvate dehydrogenase complex (PDC) deficiency is a major cause of primary lactic acidemia in children. Prompt and correct diagnosis of PDC deficiency and differentiating between specific vs generalized, or secondary deficiencies has important implications for clinical management and therapeutic interventions. Both genetic and enzymatic testing approaches are being used in the diagnosis of PDC deficiency.

Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency.

Mutations in ECHS1 result in short-chain enoyl-CoA hydratase (SCEH) deficiency which mainly affects the catabolism of various amino acids, particularly valine. We describe a case compound heterozygous for ECHS1 mutations c.836T>C (novel) and c.

Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion.

Mutations in SUCLA2 result in succinyl-CoA ligase (ATP-forming) or succinyl-CoA synthetase (ADP-forming) (A-SCS) deficiency, a mitochondrial tricarboxylic acid cycle disorder. The phenotype associated with this gene defect is largely encephalomyopathy. We describe two siblings compound heterozygous for SUCLA2 mutations, c.

Somatic mosaicism for a novel mutation in a male with severe pyruvate dehydrogenase complex deficiency.

Pyruvate dehydrogenase complex (PDC) deficiencies are mostly due to mutations in the X-linked gene. Males with hemizygous mutations are clinically more severely affected, while those with mosaic mutations may manifest milder phenotypes. We report a patient harboring a novel, mosaic missense mutation, c.

Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity.

The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders.

Review of clinical trials for mitochondrial disorders: 1997-2012.

Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q10 (CoQ10; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ10), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ10), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes).

Design and implementation of the first randomized controlled trial of coenzyme CoQ₁₀ in children with primary mitochondrial diseases.

We report the design and implementation of the first phase 3 trial of CoenzymeQ₁₀ (CoQ₁₀) in children with genetic mitochondrial diseases. A novel, rigorous set of eligibility criteria was established. The trial, which remains open to recruitment, continues to address multiple challenges to the recruitment of patients, including widely condoned empiric use of CoQ₁₀ by individuals with proven or suspected mitochondrial disease and skepticism among professional and lay mitochondrial disease communities about participating in placebo-controlled trials.

Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype.

Pyruvate dehydrogenase complex (PDC) deficiency is a relatively common mitochondrial disorder that primarily presents with neurological manifestations and lactic acidemia. We analyzed the clinical outcomes and neurological features of 59 consented symptomatic subjects (27 M, 32 F), who were confirmed to have PDC deficiency with defined mutations in one of the genes of PDC (PDHA1, n = 53; PDHB, n = 4; DLAT, n = 2), including 47 different mutations, of which 22 were novel, and for whom clinical records and/or structured interviews were obtained. 39% of these subjects (23/59) have died.

High prevalence of overweight and obesity in females with phenylketonuria.

The primary treatment for phenylketonuria (PKU) is a low phenylalanine diet together with an amino acid-based, phenylalanine-free formula. Thus, PKU patients tend to consume a diet enriched in carbohydrates which could predispose to obesity. Studies in the 1980s and 1990s demonstrated that school-age phenylketonuria (PKU) patients have a higher mean body weight compared to a control population.

Deletion at chromosomal band Xp22.12-Xp22.13 involving PDHA1 in a patient with congenital lactic acidosis.

We present a patient with congenital lactic acidosis, agenesis of the corpus callosum, and profound developmental delay. Assays of pyruvate dehydrogenase complex function were normal in lymphocytes, but decreased in fibroblasts. Sequencing of the PDHA1 gene did not reveal deleterious mutations, and BAC based microarray analysis did not reveal any chromosomal abnormality.

Somatic mosaicism for PDHA1 mutation in a male with pyruvate dehydrogenase complex deficiency.

Pyruvate dehydrogenase complex deficiency is a clinically heterogeneous disorder. Most cases are due to mutations in an X-linked PDHA1 gene encoding the E1alpha subunit of the multienzyme complex. Females with mutations in the PDHA1 gene may be asymptomatic or have a milder phenotype as a result of skewed X-inactivation, while males are typically more severely affected.

Establishing a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium.

The Urea Cycle Disorders Consortium (UCDC) was created as part of a larger network established by the National Institutes of Health to study rare diseases. This paper reviews the UCDC's accomplishments over the first 6years, including how the Consortium was developed and organized, clinical research studies initiated, and the importance of creating partnerships with patient advocacy groups, philanthropic foundations and biotech and pharmaceutical companies.

Treatment of mitochondrial electron transport chain disorders: a review of clinical trials over the past decade.

While many treatments for mitochondrial electron transport (respiratory) chain disorders have been suggested, relatively few have undergone controlled clinical trials. This review focuses on the recent history of clinical trials of dichloroacetate (DCA), arginine, coenzyme Q(10), idebenone, and exercise in both primary (congenital) disorders and secondary (degenerative) disorders. Despite prior clinical impressions that DCA had a positive effect on mitochondrial disorders, two trials of diverse subjects failed to demonstrate a clinically significant benefit, and a trial of DCA in MELAS found a major negative effect of neuropathy.

Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2.

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait.

Cross-sectional multicenter study of patients with urea cycle disorders in the United States.

Inherited urea cycle disorders comprise eight disorders (UCD), each caused by a deficiency of one of the proteins that is essential for ureagenesis. We report on a cross-sectional investigation to determine clinical and laboratory characteristics of patients with UCD in the United States. The data used for the analysis was collected at the time of enrollment of individuals with inherited UCD into a longitudinal observation study.

Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy.

Unlabelled: MPV17 is a mitochondrial inner membrane protein of unknown function recently recognized as responsible for a mitochondrial DNA depletion syndrome. The aim of this study is to delineate the specific clinical, pathological, biochemical, and molecular features associated with mitochondrial DNA depletion due to MPV17 gene mutations. We report 4 cases from 3 ethnically diverse families with MPV17 mutations.

Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children.

Objective: Open-label studies indicate that oral dichloroacetate (DCA) may be effective in treating patients with congenital lactic acidosis. We tested this hypothesis by conducting the first double-blind, randomized, control trial of DCA in this disease.

Methods: Forty-three patients who ranged in age from 0.

A nonsense mutation of PEPD in four Amish children with prolidase deficiency.

Encoded by the peptidase D (PEPD) gene located at 19q12-q13.11, prolidase is a ubiquitous cytosolic enzyme that catalyzes hydrolysis of oligopeptides with a C-terminal proline or hydroxyproline. We describe here four Amish children with a severe phenotype of prolidase deficiency in the Geauga settlements of Ohio as the first report of prolidase deficiency in the Amish population as well as in the United States.

Somatic mosaicism in a male with an exon skipping mutation in PDHA1 of the pyruvate dehydrogenase complex results in a milder phenotype.

Pyruvate dehydrogenase complex (PDC) deficiency is commonly due to mutations of PDHA1 on the X chromosome. Milder phenotypic manifestations occur in heterozygous females than in hemizygous males with the same mutation, and females are more likely to survive with severe mutations. The boy described here had hypotonia, moderate developmental delay, tremors, normal growth and brain MRI, and normal to slightly elevated lactate.

Oxidative phosphorylation analysis: assessing the integrated functional activity of human skeletal muscle mitochondria--case studies.

Oxidative phosphorylation analysis, performed on freshly-isolated mitochondria, assesses the integrated function of the electron transport chain (ETC) coupled to ATP synthesis, membrane transport, dehydrogenase activities, and the structural integrity of the mitochondria. In this review, a case study approach is employed to highlight detection of defects in the adenine nucleotide translocator, the pyruvate dehydrogenase complex, fumarase, coenzyme Q function, fatty acid metabolism, and mitochondrial membrane integrity. Our approach uses the substrates glutamate, pyruvate, 2-ketoglutarate (coupled with malonate), malate, and fatty acid substrates (palmitoylcarnitine, octanoylcarnitine, palmitoyl-CoA (with carnitine), octanoyl-CoA (with carnitine), octanoate and acetylcarnitine) in addition to succinate, durohydroquinone and TMPD/ascorbate to uncover metabolic defects that would not be apparent from ETC assays performed on detergent-solubilized mitochondria.

Autosomal dominant acute necrotizing encephalopathy maps to 2q12.1-2q13.

In autosomal dominant acute necrotizing encephalopathy (ADANE), apparently healthy children develop necrotizing lesions in their thalami and brainstems in the course of febrile illnesses. We used DNA from affected subjects and obligate carriers to map ADANE to a 6.5Mb region on chromosome 2.

Gene therapy for pyruvate dehydrogenase E1alpha deficiency using recombinant adeno-associated virus 2 (rAAV2) vectors.

To determine the feasibility of gene transfer to correct defects in the E1alpha subunit of the pyruvate dehydrogenase (PDH) complex (PDC), we constructed rAAV vectors that expressed PDH E1alpha, either alone or with a green fluorescent protein tag, from a hybrid cytomegalovirus (CMV) enhancer/chicken beta-actin (CB) promoter. These vectors were functional in vitro, as judged by increased expression of mRNA in vector-transduced deficient cell lines and correction of the biochemical defect in PDH activity in these cells. Approximately 30% of wild-type levels of PDH activity were restored under conditions with which only about 15% of cells were transduced.